Basics
What are the histologic subtypes of RCC?
* Clear cell (75% incidence--usually associated with VHL mutation).
* Papillary--High grade (10% incidence--usually associated with FH mutation i.e fumarate hydratase)
* Papillary--Low grade (5% incidence--associated with MET muatation)
* Chromophobe (5% incidence--associated with FLCN mutation)
Checkmate 214 study?
Hint: Adjuvant therapy in localized and oligometastatic disease.
Treatment-naive metastatic clear cell RCC
Arm A Arm B
Nivo (3mg/kg)+Ipi(1 mg/kg) Sunitinib
Q 3W x 4 doses, then nivo (3 mg/kg)IV
Q2 weeks--treatment until progression or
unacceptable toxicity.
Results-----> Favorable group--> Similar OS, PFS favoured sunitinib.
Poor and intermediate group--> Improved OS and PFS with nivo + ipi.
What is the recommended adjuvant therapy after nephrectomy for patients with non-metastatic high-risk renal cell carcinoma?
Adjuvant pembrolizumab (anti-PD-1 immunotherapy) is the preferred option for eligible patients with high-risk clear cell RCC after complete resection.
The choice of adjuvant pembrolizumab 200 mgQ3 weeks~1 year(<=17 cycles) is based on the KEYNOTE-564 trial, which demonstrated improved disease-free survival and overall survival? in this population.
Intermediate-risk features typically include:
--> pT2, grade 4 or sarcomatoid features, N0
-->pT3, any grade, N0
High risk of recurrence:
--> pT4, any grade, N0
--> Any pT, any grade, N+
M1 NED Metastatectomy within 1 year of nephrectomy were also included in the trial. {NED = No Evidence of Disease }
The patients were ECOG PS 0-1.
IMDC prognostic score?
Factors-->
1) KPS<80
2) Dx to treatment less than 1 year
3) Anemia
4) Leukocytosis
5) Thrombocytosis
6) Hypercalcemia
Favourable--0 factors [mOS 37 months~ 3years, 1 month]
Intermediate--1-2 factors [mOS 27 months ~ 2 years, 3 months]
Poor-- 3-6 factors [mOS 8.8 months]
First-line therapy for relapse or stage IV disease?
Both favorable and poor/intermediate groups:
IO TKI regimens
--> Axitinib+pembrolizumab
--> Cabozantinib+nivolumab
--> Lenvantanib+pembrolizumab
IO IO regimen
--> ipilimumab + nivolumab
------------------
--> For poor/intermediate, we also have Cabozantinib alone for patients who didn't tolerate IO therapy.
True or false?
IO TKI regimens will have a higher probability of upfront response as compared to IO-IO regimens.
True
Name a cancer Prediction tool that provides a numerical estimate of the probability of disease-free and overall survival in patients with RCC?
ASSURE RCC Prognostic Nomogram.
Subsequent therapy for clear cell RCC for relapse or stage IV disease in patients who are IO therapy naive? Name any four regimens.
If they are IO naive---Give IO
--> Ipi nivo
--> Axi Pem
--> Len Pem
--> Cabo Nivo
--> Everolimus + Lenvatinib
--> Nivo alone
--> Cabo alone
True or false
Ipi+nivo is not a highly powerful regimen for patients with extensive bone mets?
True!
RCC Staging?
Non-Metastatic
Stage 1--> T1N0M0---> <7 cm, confined.
Stage II--> T2N0M0---> > 7 cm, confined
Stage III--> T1-2, N1 or T3, N0-1
TIIIa--> extracapsular extension or renal vein.
TIIIb --> Renal vein below the diaphragm.
TIIIC--> Renal vein above the diaphragm or invading vein wall.
N1 --> regional nodes involved.
Metastatic disease
Stage IV--> T4(any N or M) or M1 {T4 is extension beyond gerota's fascia}
Subsequent therapy for clear cell RCC for relapse or stage IV disease in patients who have been exposed to IO therapy? Name any four regimens.
--> Axitinib
--> Cabozantinib
--> Belzutifan [hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor]
--> Everolimus + Lenvatinib
True or False?
In favourable risk individuals trial comparing IO-IO [Ipi+Nivo] and sunitinib showed similar overall survival, but sunitinib had better progression-free survival.
True.
In the favorable-risk subgroup of CheckMate‑214 (ipilimumab + nivolumab vs sunitinib):
Overall Survival was similar between the two groups — no statistically significant difference.
Progression‑Free Survival actually favored sunitinib, with better median PFS compared to the IO‑IO arm.
To restate: in favorable-risk patients, Ipi + Nivo did not outperform sunitinib in OS and had inferior PFS, so sunitinib showed better PFS.
True-false?
1) IO-IO and IO-TKI regimens have OS and PFS benefits in the poor and intermediate-poor risk groups.
2) IO-TKI regimens have no OS benefit but PFS benefit in the favourable group.
3) IO-IO regimen has no OS and PFS in the favorable group?
4) For patients with a threatening disease, where an immediate response is desired, is the IO-TKI regimen better?
1) True
2) True
3) True
4) True